Alzheimer's disease

Studies in mice by scientists at St. Jude Children’s Research Hospital point to a potential new approach to treating Alzheimer’s disease (AD), and possibly other human diseases including cancer. Their studies focused on proteins involved in autophagy—the normal process by which cells recycle components during periods of stress or energy deprivation—and on the role of LC3-associated endocytosis (LANDO) in neuroinflammation.

“This work solidifies LC3-associated endocytosis as a pathway that prevents inflammation and inflammatory cytokine production in the central nervous system,” said Bradlee Heckmann, PhD, the John H. Sununu endowed fellow at St. Jude. “While much of the data on LANDO suggests a significant role in neuroinflammatory and neurodegenerative diseases, there is also a strong possibility that it could be targeted as a therapy against cancer or even infectious diseases that rely on similar processes for survival.”

Heckmann is first author of the team’s published paper in Science Advances, which is titled, “Noncanonical function of an autophagy protein prevents spontaneous Alzheimer’s disease.”

Previous research has identified roles for autophagy in suppressing the pathogenesis of neurodegenerative conditions, including Alzheimer’s disease, and scientists have reported that the expression of components of the autophagy machinery decline both with aging and in the AD brain, which highlights the importance of the process in homeostasis, the authors noted. “Autophagy and pathways that use the autophagy machinery are known to function in the regulation of amyloid generation, neuronal homeostasis, and ß-amyloid (Aß) clearance,” they wrote. “However, many autophagy proteins perform functions distinct from canonical autophagy.”

The researchers had previously discovered the LANDO pathway in microglial cells, the primary immune cells of the brain and central nervous system. Scientists have found that when genes required for this pathway are deleted, Alzheimer’s disease progression accelerates in a mouse model. “Previously, we demonstrated that ablation of components of LANDO in microglia markedly exacerbate AD pathology in a transgenic murine model,” they explained.

The investigators also showed that LANDO protects against neuroinflammation, one of the hallmarks of Alzheimer’s disease. Continuing to investigate LANDO, they identified a novel function of the protein ATG16L, which is critical for autophagy. While ATG16L is important for autophagy, it can also play a role in LANDO. The investigators found that if a region of ATG16L called the WD domain is deleted, LANDO is inhibited while autophagy continues.

Mouse models used in Alzheimer’s disease research generally rely on making genetic changes that recreate the disease. For this work, researchers used a new model with a specific deficiency of just the WD domain of ATG16L. In these animals, autophagy continues normally, but the LANDO pathway is lacking. By the time the mice are two years old, they exhibit symptoms and pathology that mimic human Alzheimer’s disease.

This spontaneous age-associated model of Alzheimer’s disease is the first created by deleting a single protein domain—WD on ATG16L—not previously associated with Alzheimer’s disease. “Our findings reported herein indicate that deletion of a single domain of the autophagy protein Atg16L, required for LANDO, is sufficient for driving spontaneous, age-associated AD pathology in mice,” they wrote.

“We learned about this pathway in the context of brain tumor research, but it has major implications for neuroinflammatory and neurodegenerative disease,” said senior author Douglas Green, PhD, chair of the St. Jude immunology department. “We’ve shown that deficiency in LANDO, combined with aging, can lead to Alzheimer’s disease in a unique mouse model, and there is evidence suggesting that this could also be the case in humans.”

The researchers analyzed human Alzheimer’s disease tissue samples, looking at the expression of proteins that regulate LANDO, including ATG16L. They found that expression of these proteins is decreased by more than 50% in people with Alzheimer’s disease. The finding provides a correlation between how deficiency in LANDO, combined with aging, may lead to Alzheimer’s disease in the mouse model and in humans. “Although these data are not sufficient to directly link defects in the LANDO machinery with AD establishment in humans,” they noted, “they do illustrate a relationship between the expression of the LANDO machinery and AD that is correlative to disease pathology in the spontaneous age-associated AD observed in the Atg16L WD-deficient mouse.”

Reducing neuroinflammation has been proposed as a potential way to treat Alzheimer’s disease. The researchers’ tested whether they could treat their new mouse model, using a compound that inhibits the inflammasome—a complex of proteins that activates pro-inflammatory immune reactions. “Inflammasome inhibition has been proposed as a putative therapeutic approach that reduces neuroinflammation and Tau phosphorylation,” they noted.

The scientists targeted the inflammasome that is responsible for neuroinflammation in people with Alzheimer’s disease, using an inflammasome inhibitor, MCC950. When they profiled the animals’ behavior and responses to standard tests, after treatment, they found evidence of improved cognition and memory in addition to a decrease in neuroinflammation. “…mice treated with MCC950 had a restoration in their behavioral and memory capacity, approaching that of wildtype littermates …” they noted.

“It is clear that exacerbated and sustained neuroinflammation is a key component in the establishment and progression of AD and that noncanonical functions of the autophagy machinery in pathways such as LANDO, which are correlative to AD in humans, are critical regulators of inflammatory activation in response to Aß,” the investigators concluded. “The mechanism by which LANDO is able to link Aß recognition with inflammatory regulation remains elusive; however, it is plausible that the reduced recycling of Aß receptors leads to sustained intracellular signaling following receptor activation.”

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